TY - JOUR
T1 - Joint effect of insulin-like growth factors and mutagen sensitivity in lung cancer risk
AU - Wu, Xifeng
AU - Yu, He
AU - Amos, Christopher I.
AU - Hong, Waun K.
AU - Spitz, Margaret R.
N1 - Funding Information:
The study was supported by the National Institutes of Health grants U19 CA 68437 to Dr Waun K. Hong, ROl CA 55769 to Dr Margaret R. Spitz, and lRO1 CA 74880-OlA2 to Dr Xifeng Wu. Dr Waun K. Hong is an American Cancer Society Clinical Research Professor.
PY - 2000/5/3
Y1 - 2000/5/3
N2 - Background: We hypothesize that accumulation of genetic damage is dependent on an individual's intrinsic carcinogen sensitivity and on various humoral factors (e.g., insulin-like growth factors [IGFs]) that enhance proliferation, resistance to apoptotic cell death, and clonal outgrowth of genetically damaged cells. We tested this hypothesis by determining whether proliferation potential and genetic instability are associated with the risk of lung cancer. Methods: In a study of 183 lung cancer patients and 227 matched control subjects, we examined the joint effects of latent genetic instability (measured as mutagen sensitivity) and elevated proliferation potential (assessed by measuring IGFs) in lung cancer risk. Levels of IGF-I, IGF-II, and IGF-binding protein-3 (IGFBP-3) in plasma were measured by use of immunoassay kits. Mutagen sensitivity was assessed by quantitating bleomycinand benzo[a]pyrene diol epoxide (BPDE)-induced chromatid breaks in peripheral blood lymphocyte cultures. Results: Although not statistically significant, the mean levels of IGF-I and the molar ratio of IGF-I/IGFBP-3 were higher in patients with advanced or poorly differentiated disease than in patients with early or well-differentiated disease. Variation in IGFs was not associated with any specific histologic type or tumor stage. High levels of IGF-I and enhanced mutagen sensitivity were individually associated with increased risk of lung cancer: odds ratio (OR) of 2.13 (95% confidence interval [CI] = 1.20-3.78) for IGF-I, 2.50 (95% CI = 1.49-4.20) for bleomycin sensitivity, and 2.95 (95 % CI = 1.72-5.06) for BPDE sensitivity. The OR was statistically significantly elevated to 8.88 for both higher IGF-I and bleomycin sensitivity (95% CI = 3.67-21.50) and to 13.53 for higher IGF-I and BPDE sensitivity combined (95% CI = 4.4840.89). With all three risk factors considered together, the OR was 17.09 (95% CI = 4.16-70.27). High levels of IGFBP-3 alone were associated with reduced lung cancer risk: OR = 0.59 (95% CI = 0.33-1.05). Conclusions: Our data suggest that individuals with genetic instability and higher proliferation potential are at enhanced risk for lung cancer.
AB - Background: We hypothesize that accumulation of genetic damage is dependent on an individual's intrinsic carcinogen sensitivity and on various humoral factors (e.g., insulin-like growth factors [IGFs]) that enhance proliferation, resistance to apoptotic cell death, and clonal outgrowth of genetically damaged cells. We tested this hypothesis by determining whether proliferation potential and genetic instability are associated with the risk of lung cancer. Methods: In a study of 183 lung cancer patients and 227 matched control subjects, we examined the joint effects of latent genetic instability (measured as mutagen sensitivity) and elevated proliferation potential (assessed by measuring IGFs) in lung cancer risk. Levels of IGF-I, IGF-II, and IGF-binding protein-3 (IGFBP-3) in plasma were measured by use of immunoassay kits. Mutagen sensitivity was assessed by quantitating bleomycinand benzo[a]pyrene diol epoxide (BPDE)-induced chromatid breaks in peripheral blood lymphocyte cultures. Results: Although not statistically significant, the mean levels of IGF-I and the molar ratio of IGF-I/IGFBP-3 were higher in patients with advanced or poorly differentiated disease than in patients with early or well-differentiated disease. Variation in IGFs was not associated with any specific histologic type or tumor stage. High levels of IGF-I and enhanced mutagen sensitivity were individually associated with increased risk of lung cancer: odds ratio (OR) of 2.13 (95% confidence interval [CI] = 1.20-3.78) for IGF-I, 2.50 (95% CI = 1.49-4.20) for bleomycin sensitivity, and 2.95 (95 % CI = 1.72-5.06) for BPDE sensitivity. The OR was statistically significantly elevated to 8.88 for both higher IGF-I and bleomycin sensitivity (95% CI = 3.67-21.50) and to 13.53 for higher IGF-I and BPDE sensitivity combined (95% CI = 4.4840.89). With all three risk factors considered together, the OR was 17.09 (95% CI = 4.16-70.27). High levels of IGFBP-3 alone were associated with reduced lung cancer risk: OR = 0.59 (95% CI = 0.33-1.05). Conclusions: Our data suggest that individuals with genetic instability and higher proliferation potential are at enhanced risk for lung cancer.
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U2 - 10.1093/jnci/92.9.737
DO - 10.1093/jnci/92.9.737
M3 - Article
C2 - 10793110
AN - SCOPUS:0034600258
SN - 0027-8874
VL - 92
SP - 737
EP - 743
JO - Journal of the National Cancer Institute
JF - Journal of the National Cancer Institute
IS - 9
ER -